The HIV envelope protein, gp120, mediates entry of viral particles into CD4+ T cells. This process requires that gp120 binds to both the CD4 receptor and a co-receptor, either CCR5 or CXCR4. Because gp120 is the only viral protein against which neutralizing antibodies are elicited, it is a key component of a potential AIDS vaccine. We have recently identified the integrin alpha4-beta7 as an additional HIV receptor on the surface of CD4+ T cells. The alpha4-beta7 receptor is the principal integrin involved in lymphocyte homing to the lamina propria of gut-associated lymphoid tissue (GALT), a site of considerable HIV replication especially during acute infection. Our observations suggest that the direct interaction between HIV gp120 and alpha4-beta7 provides a plausible mechanistic explanation for the preferential establishment and/or maintenance of HIV replication in GALT. Our current work is focused on the role of alpha4-beta7 integrin in HIV transmission. We are uncovering evidence indicating that transmitting viruses are specifically adapted to interact with alpha4-beta7 expressing CD4+ T cells. Under certain circumstances, we are finding that the envelope proteins of transmitting viruses interact differently with the CD4 receptor and alpha4-beta7 than do the envelopes of viruses replicating at later stages of disease. More specifically, our findings reveal that transmitting gp120s interact more efficiently with alpha4-beta7 and less efficiently with CD4 than other envelopes. In addition, the transmitting gp120s appear to exhibit unique structural properties that we have not yet fully characterized. These observations may provide important new information that will aid in the development of an effective vaccine to prevent HIV acquisition.